Do chronic myeloid leukemia patients with late "warning" responses benefit from "watch and wait" or switching therapy to a second generation tyrosine kinase inhibitor?

In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as "warning responses." In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR(4.5) ): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P = <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival.

Clinical Findings and Outcomes From Subjects With COVID-19 Pneumonia in an Intermediate Respiratory Care Unit.

BACKGROUND: Many patients with COVID-19 require respiratory support and close monitoring. Intermediate respiratory care units (IRCU) may be valuable to optimally and adequately implement noninvasive respiratory support (NRS) to decrease clinical failure. We aimed at describing intubation and mortality in a novel facility entirely dedicated to COVID-19 and to establish their outcomes. METHODS: This was a retrospective, observational study performed at one hospital in Spain. We included consecutive subjects age > 18 y, admitted to IRCU with COVID-19 pneumonia, and requiring NRS between December 2020-September 2021. Data collected included mode and usage of NRS, laboratory findings, endotracheal intubation, and mortality at day 30. A multivariable Cox model was used to assess risk factors associated with clinical failure and mortality. RESULTS: A total of 1,306 subjects were included; 64.6% were male with mean age of 54.7 y. During the IRCU stay, 345 subjects clinically failed NRS (85.5% intubated; 14.5% died). Cox model showed a higher clinical failure in IRCU upon onset of symptoms and hospitalization was < 10 d (hazard ratio [HR] 1.59 [95% CI 1.24-2.03], P < .001) and PaO2 /FIO2 < 100 mm Hg (HR 1.59 [95% CI 1.27-1.98], P < .001). These variables were not associated with increased 30-d mortality. CONCLUSIONS: The IRCU was a valuable option to manage subjects with COVID-19 requiring NRS, thus reducing ICU overload. Male sex, gas exchange, and blood chemistry at admission were associated with worse prognosis, whereas older age, gas exchange, and blood chemistry were associated with 30-d mortality. These findings may provide a basis for better understanding outcomes and to improve management of noninvasively ventilated patients with COVID-19.

Synthesis and evaluation of 2-substituted-6-phenyl-4,5-dihydropyridazin-3(2H)-ones as potent inodilators.

The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was achieved by Friedel-Crafts acylation of appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (10-6 mol L-1). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC50 = 0.08 +/- 0.01 mumol L-1).

Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months.

Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar.

Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.

Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone are reported. An effect of substitution at 2-position of pyridazinone ring on vasodilatory potential has also been explored. The most active compound 6-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-2-(4-fluorophenyl)-4,5-dihydropyridazin-3(2H)-one (11) exhibited vasodilating activity in nanomolar range (IC(50)=0.051 microM).

[Panniculitic T-cell lymphoma]. / Linfoma de células T paniculítico.

Panniculitic T-cell lymphoma is a rare, aggressive variant of cutaneous T-cell lymphoma, with fewer than 100 cases described. The main problem is its diagnosis, as both the clinical and the histological features may simulate benign panniculitis. We present the case of a 34-year-old male patient, who had presented with an indurated plaque, sclerodermiform in appearance, on the front of the right thigh for 4 months, later accompanied by fever and constitutional symptoms. The initial diagnosis was cellulitis, but no clinical improvement was seen despite systemic antibiotic therapy. After two skin biopsies, the patient was diagnosed with panniculitic cutaneous T-cell lymphoma. The patient was treated with 8 cycles of CHOP chemotherapy, with resolution of the symptoms.